Benzo{a}pyrene is a potent mutagen/carcinogen that is metabolically activated inside cells, including to its (+)-anti-7,8-diol-9,10- epoxide [(+)-anti-B[a]PDE, which gives DNA adducts, principally a N2-dG. We showed that (+)-anti-B[a]PDE able to induce such a diverse array of mutations? Base substitution mutations predominate, and principally occur at G:C base pairs, where GC->TA, GC->AT and GC->CG are all significant (57%, 23%, 20%, respectively). We have done molecular biological/mutagenesis work to show that (+)-trans-antiB[a]P-n2-Gus is capable of inducing a preponderance of G->T mutations (> approximately 95 percent) in 5'-TGC sequences, or a preponderance of G->A mutations (->approximately 95 percent) in a 5'-AGA sequence. This raises the question: how can a single entity [i.e., (+)-trans-anti-B[a]P-N2-Gua] induce a different pattern of mutations depending on sequence context? Our working hypothesis has been that adduct mutational complexity is due to adduct conformational complexity, and that adduct conformation and, thereby, mutation is controlled by various factors, notably, DNA sequence context. To study adduct conformation, we did molecular modeling, and found that, based on first principles, (=)-trans-anti-B[a]P-N2-Gua can adopt at least 16 conformations. This is a large number, and probably all are not relevant to base substitutions mutagenesis, we have used a combination of common sense and the results of our molecular mechanical calculations to conclude that three conformations are most likely to be relevant to mutagenesis. Furthermore, we noticed a correlation. In a sequence where G->T mutations predominated (5'-TGC) a base displaced conformation of (+)-trans-anti-B[a]P-N2-Gua with the dG moiety in the major groove (Gma5) was calculated to be lower in energy. In two sequences where we observed G->A mutations were found more equally (5'-CGG, 5'-GGG) Gma5 and Gmi3 were calculated to be more similar in energy. This correlation suggests the hypothesis that Gma5 is the conformation responsible for G->T mutations and Gmi3 is responsible for G->A mutations. We are pursuing this hypothesis in molecular biological/mutagenesis studies (funded separately). Herein we propose three specific aims to pursue this hypothesis using molecular modeling and computational chemical techniques.